Acute lung injury (ALI) most commonly occurs after severe bacterial infections such as pneumonia or sepsis. An clear impediment to successful ALI therapy resides in a complex disease course often characterized by an initial burst in host inflammation from pro- inflammatory mediators resulting in extensive tissue injury; a second phase of immunosuppression ensues that poses risks for secondary bacterial infections. IL-1 ?, generated by the inflammasome and invasive bacterial infections both contribute to disease pathobiology and illness severity. The mechanistic platform of this proposal resides on our discovery of a unique molecular model of inflammation whereby a relatively new protein, Fbxo3, potently triggers IL-1 ? release from human inflammatory cells after bacterial infection by destabilizing a crucial inflammasome inhibitor, Fbxl2. By targeting the ApaG molecular signature present in both host Fbxo3 and many bacteria, we developed a first-in-class genus of small molecule inhibitors that display dual anti-inflammatory and anti-bacterial activity in murine ALI models. Hence, in this application we will first elucidate how bacterial pathogens transcriptionally activate Fbxo3, allowing the protein to eliminate an inflammasome inhibitor, Fbxl2 (Aim 1). We will specifically elucidate how Fbxl2 targets the NALP7 inflammasome. Next we will optimize the pharmacologic design and test a novel small molecule that exhibits distinct, and yet complementary anti-inflammatory and anti-bacterial properties in ALI models (Aim 2). These studies will provide a new mechanistic pathway of innate immunity that will serve as a basis to fulfill an unmet therapeutic need in subjects with altered immune responses during critical illness.